PROJECT SUMMARY/ABSTRACT Among the Neglected Tropical Diseases that continue to afflict the ?bottom billion? of the world's population, schistosomiasis ranks as one of the most common (currently 258 million cases) and difficult to control. Sub- Saharan Africa now supports over 85% of the world's cases of schistosomiasis, a disease that has long been underestimated in its impact on the people it infects, often impoverished children. The WHO has called for the elimination of human schistosomiasis as a public health problem by 2025, and although chemotherapy with the one available drug praziquantel will remain the backbone of this effort, a consensus has emerged that integrated control approaches (including snail control) will be needed if we are to achieve the WHO's ambitious goals. Nowhere is the prospect for schistosomiasis control more daunting than in the African great lakes like Lake Victoria and Lake Albert in which Schistosoma mansoni thrives, being transmitted in and around such habitats by at least three taxa of Biomphalaria snails. Building on a long-standing partnership between the University of New Mexico and the Kenya Medical Research Institute, we hypothesize that inherent biological differences among the three snail taxa lead to differences in compatibility with schistosomes and other parasites, and create for each taxon distinct opportunities for controlling the larval stages of S. mansoni that can propagate within them. We propose three aims: Aim 1) To reveal and dissect the roles of different Biomphalaria taxa with marked biological differences in the transmission of S. mansoni in six representative transmission sites in the Lake Victoria basin. The three taxa are B. sudanica (an out-crossing, shoreline- inhabiting species), B. choanomphala (a deep water ecophenotype of B. sudanica) and B. pfeifferi (a self- fertilizing snail usually in streams leading into the lake); Aim 2) To define and exploit the biodiversity of non- schistosome digeneans in the Lake Victoria basin, to compete with and suppress S. mansoni infections within Biomphalaria; and Aim 3) To develop novel approaches for snail or larval schistosome control scalable to vast transmission sites like Lake Victoria. These attempts will include identification and testing of schistosome- resistant snails and development of CRISPR/Cas technology with African Biomphalaria snails such that the knowledge can eventually be exploited for multiple purposes, including novel approaches for snail control. Our proposed studies offer the prospect of developing snail control that can be synchronized with integrated schistosomiasis control strategies, exploit local resources that could be scaled up and applied in low tech ways, and provide key training for young investigators in both the U.S. and Kenya for the challenges that lie ahead for snail-centered schistosomiasis control.